My Induction as President of the American Cancer Society

On November 15, I had the honor of becoming President of the American Cancer Society in its 100th anniversary year.

My induction took place during the Society's Nationwide Volunteer and Staff Leadership Summit in Atlanta. Gary M. Reedy, worldwide vice president of government affairs and policy at Johnson & Johnson and an active Society volunteer for twelve years, was installed as chair of the Board of Directors during the same ceremony. We also added eleven new officers to the board: Pamela K. Meyerhoffer, F.A.H.P., of Litchfield Park, Arizona, chair-elect; Tim E. Byers, M.D., M.P.H., of Arvada, Colorado, president-elect; Robert E. Youle, of Evergreen, Colorado, vice chair; Douglas K. Kelsey, M.D., Ph.D., F.A.A.P., of Zionsville, Indiana, first vice president; Enrique Hernandez, M.D. of Penn Valley, Pennsylvania, second vice president; Daniel P. Heist, C.P.A., of State College, Pennsylvania, treasurer; Robert R. Kugler, Esq. of Haddonfield, New Jersey, secretary; W. Phil Evans, M.D., F.A.C.R., of Dallas, Texas, immediate past president; and Cynthia M. LeBlanc, Ed.D., of Richmond, California.
 
I'm sure you'll be hearing a lot more about my work with Gary, the board, and the ACS over the course of the next year.

Oh, and the mystery man in the picture is my brother, Ernie, who flew in for the occasion.

UK Citizens denied Ipilimumab

"Not so NICE" has done it again. On October 14, NICE, the UK's National Institute of Clinical Excellence, announced that it will not approve the use of Yervoy (ipilimumab), for the treatment of unresectable stage III and IV melanoma, despite a randomized trial showing improvement in survival in a situation where there is no effective treatment.

NICE used it's usual excuse: "It is not cost effective."

Almost twice as many patients treated with Yervoy are alive at one year. But, in a news release, NICE chief executive Andrew Dillon criticized the results of the study, saying that Yervoy (ipilimumab) had not been compared to the drugs currently used to treat stage III or IV melanoma.

In U.K. practice, like the rest of the world, this is carboplatin-based chemotherapy, dacarbazine, or supportive care. Will everyone who has seen a good response to the above treatment please raise their hands? I haven't in years, and neither has anyone else.

Where do a bunch of inexperienced bureaucrats get off telling the world's experts how to treat their patients?

Ipilimumab has already been approved by the US FDA and EMA. Very exciting things are happening in melanoma treatment these days and if you have the disease, you want to have the chance to be around to benefit from recent advances. Yervoy (ipilimumab) is one of them.

I guess Britons with advanced melanoma will have to watch from afar. Do they understand that they're being denied the right to live?

The National Cancer Institute's Broken Clinical Trials Program and The New York Times

There was an editorial in The New York Times last week on a report by the Institute of Medicine on the NCI's clinical trials program and its difficulties. The editorial made the point that the clinical trials effort is at the heart of transferring technology to cancer patients, and that it needs fixing.

The IOM report and the editorial missed the major problem, however. So did the letters to the editor on Sunday 2 May from Drs Doug Blayney and Alan Lichter, on behalf of the American Sociey of Clinical Oncology, and from Dr  Bruce Chabner, Clincal Director at Massachusetts General Hospital Cancer Center in Boston.

Blayney and Lichter extoll the virtues of the clinical cooperative groups and claim that the problem is money. They are underfunded, they say. True. Chabner points out that the  NCI's cooperative group program is no longer the main instrument for developing new treatments anyhow. Also true. (In fact they never were. But that's another story.)

But everybody missed the main source of the problem: over regulation.

Apparently this is too much of a lightning rod for people to discuss in public. Over regulation, in the name of patient safety, affects both cooperative group and industry studies. In the name of protecting patients from harm they stifle new developments and instead "protect" patients from access to new treatments.

I refer the reader to an editorial I wrote on this subject in 2009 for Nature Reviews Clinical Oncology and reprinted on this blog shortly thereafter. Pumping money into the archaic mechanisms of doing clinical trials in NCI's cooperative groups won't do an ounce of good if the structural problems aren't fixed first.

A Possible Breakthrough: Personalized Treatment for Hodgkin's Disease

My friend and colleague, Jose Costa, and I recently had an opportunity to write an editorial about  an exciting paper by Steidl et al.  published in The New England Journal of Medicine on March 11, 2010. I thought it would be worthwhile reprinting some of our commentary here because I think the data may be what we've been looking for when it comes to changing the direction of the treatment of Hodgkin's disease. 

The data provided by Steidl and his colleagues, in fact, offer the breakthrough we have been looking for to select patients with a particularly poor prognosis, regardless of stage, for more-aggressive treatment and bring more logic to the treatment of this very curable malignancy.

Steidl and his co-authors discovered a gene signature of tumor associated macrophages and monocytes in patients with Hodgkin’s disease that correlated with outcome. Remarkably, they were able to validate the correlation in an independent cohort of patients using CD 68—an immunohistochemical marker of normal macrophages. 

  
The correlation of CD 68 positive macrophages with outcome was striking. All patients with limited disease, minimally positive for CD 68, were alive and free of disease at the time of the report. The association of CD 68 positivity and disease specific mortality rates was strong in all subsets analyzed. In advanced disease the correlation between macrophage number and progression-free survival is significant.

This study provides a rationale for the use of molecular tools when effective treatments are available but we cannot prospectively separate those who will be cured from current treatment from those who will not respond. 

Hodgkin’s disease is a good example of this type of situation. For almost 40 years now, early stage disease has been curable by radiotherapy, and combination chemotherapy can cure both early and advanced-stage disease. Despite an overall cure rate of around 80%, treatment has stagnated in the past two decades because of the absence of precise markers that can predict response to therapy. As a result of this situation most patients, especially those in early stages of disease, are over treated— they receive radiotherapy and combination chemotherapy. As a consequence, long term toxicity from treatment is significant. 

In some studies where young women have received both chemotherapy and radiotherapy, the incidence of beast cancer reaches almost 30% at 15 years after treatment. Almost all patients with classic Hodgkin disease will go into remission with initial treatment but about 30% of patients with advanced disease and almost 15% of those with early stages of disease will also relapse. Early relapses in patients with both advanced and localized disease treated with chemotherapy defines a drug resistance subset of Hodgkin’s lymphoma. This group carries a very poor prognosis through all subsequent treatment approaches including high-dose treatment with stem cell support.

It is of considerable interest that early relapse from complete remission carries the same poor prognosis in all tumor types where remission is possible, suggesting a common mechanism of resistance across tumor types. If at the time of diagnosis we could identify the small subset of Hodgkin patients who are destined to fail to respond to chemotherapy, most patients could be spared the use of a combination of modalities as initial treatment, especially radiotherapy, that is associated with long-term toxicity.    

The Reed–Sternberg (R-S) cell is unique amongst lymphoma cells in that a number of important signaling pathways have been shown to be constitutively activated, including the JAK-STAT, receptor tyrosine kinases, NF-kappa B and other pathways^. The R-S cell also secretes numerous cytokines, including granulocyte-macrophage colony-stimulating factor, which may be responsible for the assembly of inflammatory cells in involved lymph nodes. It has been termed the master regulator of the surrounding inflammatory response.

Almost all tumors types are invaded by macrophages and it was once thought that this invasion represented a host immunological response to the tumor. However, most evidence now links tumor-associated macrophages (TAM) with a poor prognosis, as demonstrated in the study by Steidl and his colleagues. Termed ‘tropic macrophages,’ TAMs bear a close resemblance in function to embryonic macrophages associated with cell migration during development.These macrophages have been shown to mediate blood vessel formation by regulating the angiogenic switch through secretion of VEGF and hypoxia inducing factor.

Migration of macrophages to areas of the tumor seems to be a late event in Hodgkin disease. It is difficult to explain the impact of trophic macrophages on response to treatment unless at some point in the evolution of the disease, a critical pathway to apoptosis is crippled in the R-S cell and this is associated with the secretion of a cytokine that leads to macrophage infiltration of the tumor. Such an event could inhibit cell death in response to cytotoxic treatments. 

Rationing Health Care is Bad for Cancer Patients

       The current bill before  the house and Senate does a disservice  for cancer patients. It is not correct to say,  " it's true that some people are covered well, but many are not" as I have heard said by people who should know better. It's more correct to say that ,"most Americans  are covered well in the current system." This is especially true of cancer patients. So be careful what you do to change it.
      Cancer patients suffer most when they try to change jobs and are denied health care in a new job because of a preexisting  condition or when the amount they can spend on health care is capped. Like most Americans, they are also concerned about cost of insurance as well.

      In prior postings I exposed the numbers game used by those who support this bill for what it was, a bogus use of numbers to scare the American people into reform they don't need and don't want. There are not 47 million Americans uninsured. Even President Obama has begun to use a lower figure, 30 million,  a little embarrassed , I think , to be caught  using a number no one bothered to check ( this is still an overestimate). The American Cancer Society should feel some embarrassment for doing the same thing.

     But what is as clear as can be is that there is no way the current House and Senate proposal can stay within budget without rationing care. And people I know close to the administration say to me " get real, Vince, rationing is coming". They barely hide this although they don't trumpet it for fear of scaring more people away. They do admit to the need to cut billions from Medicare though.
     The preferred method to decide what to ration is to use "Comparative Effectiveness Research"(CER) to decide what should be approved. A billion dollars has been allocated in the bill for this. The best way to characterize CER is to say that it compares yesterday's therapy with that of the  day before yesterday. It is always behind the curve. The newest approaches need not apply. Cancer patients always get the short end of the stick when care is rationed.
      Look at the UK's National Institute of Clinical Excellence ,(acronym ,NICE -British doctors refer to it as "not so nice"). Their decision to deny coverage for the use of the drug Erbitux in patients with head and neck cancer was one example of  a feckless disregard for cancer patients. There are more. Studies have shown an enormous, statistically significant, difference in survival for those who are irradiated with Erbitux compared with those who don't receive it. Yet they denied coverage.  They actually don't even question the data, they just say it is not cost effective to use it. In other words if you have the misfortune of having head and neck cancer in the UK, you are not worth saving.
      This is the system the bill tries to emulate. It includes commissions to determine standard of care ( in the cancer field, " standard of care" is a moving target ) and authorities to the secretary of HHS that would allow her to limit the use of new technology even without  CER, as NICE did in the UK with Erbitux. The new drug from Plexicon, to which every patient with metastatic melanoma should have access, wouldn't even be considered for CER.
      They know they will need to ration care to pay for this version of health care reform. At the most exciting time in the history of cancer research, when new clinical advances are being made every day in the cancer field these provisions would  stop clinical innovation in its tracks.

      What is needed for the cancer patient is a stepwise approach that preserves the best of the current system and provides more security . Like most people I could write a bill in  ten pages to do this, not the  2,700 pages in the current bill.
      Prevent denial of coverage for a preexisting conditions, remove caps on the amount of coverage and allow insurance to be purchased across state lines. This would do it for cancer patients and save hundreds of millions of dollars as well.
       It's the many mandates included in some state's policies that drive up cost. Purchasing across state lines would allow more people to buy less expensive policies that suit their purposes. This might mean giving up some of our precious  mandates but  isn't it is better to cover more cancer patients well, than force policies on them with too many mandates that are too expensive to buy? 

      Frankly I don't see any organizations purported to be speaking for the interests of cancer patients telling the congress the specifics of what they need and, most especially ,what they don't want. We need the three things mentioned above and we do not want  a system that will require rationing of care .

     Oh , and by the way, the Congressional Budget Office estimates the new bill would still leave 10 to 19 million people uninsured , which is more than are truly uninsured now.

What happened to the merit sytem in NIH peer review?

There was an article in the New York Times on 22 September by Gardner Harris entitled “Debate flaring over Grants research”.It was based on a recently released report by the GAO on how NIH manages its grant program.

The essence of the NYTs articcle was whether or not NIH grants administrators are right to reach down to “make exceptions “to fund grants with worse scores, to support new young investigators. They say the average age of investigators has risen from 35 in 1980 to 41today, so such steps are necessary. The American Cancer Society goes even further. Anyone over the age of 45 need not apply.

 What happened to the merit system? If your goal is to find new knowledge that leads to the eradication of disease shouldn’t we be funding the best and the brightest whatever their age?

Harris says “ There has been a growing chorus of complaints over the years that the agency's scientific review process is deficient-that is fails to finance high risk research; that projects must effectively be half done before financing is approved; that cliques control the process; and that reviewers are rarely the field’s leading lights”.

Anyone involved in the NIH grant system knows all these complaints are true. I speak from experience; I ran the largest chunk of that grant program at the NCI for 15 years.

The essence of the problem is that universities are addicted to Ro-1 grants. The grant system has become an entitlement program. Without a Ro-1 grant it is difficult for an investigator to attain tenure. What has surprised me, even shocked me, and is that what an investigator does with those grants is often secondary to the fact that they got them. Supporting high-risk research is not the major goal.
The grant peer review process has become the major arbiter of tenure. And incumbents do have an unfair advantage. Peer review committees, each made up of grantees, give the edge to established investigators like themselves. And, scientists will always admit to other scientists, (but not in public) that they don’t submit their best and newest ideas in a grant but ideas that have some data to support them- . It’s a bit of grantsmanship.

Left to their own devices, young investigators do well on their own. Their ideas are often fresh and, in a purely merit system, they can out compete an incumbent. But the way the system is now constructed they are at a disadvantage but it is a disadvantage of NIH’s own making.

The NIH distorts the system even further. It decries “targeted research” but it regularly influences the research process by issuing Request for Applications in specific (targeted) areas with set aside funds. The areas selected are what the Congress or some NIH staffer, or a board of advisors, thinks is the best way to spend grants monies. I have watched young investigators change their research interest not because they thought an RFA identified an interesting area but because they needed to follow pools of money to get a grant. So much for NIH's storied primacy of “investigator initiated research”.

And more gamesmanship. To keep Congress anxious about how many grants are funded each year NIH artificially keeps the percentage of approved grants funded very low. NIH scores grants on a system of 1 to 5 with one being the best and 5 the worst score. A grant can also be disapproved. Few ever are. Many are , however, given scores of 3, 4 or 5 that indicate they shouldn’t be funded even if the investigator is young and money is available. Or expressed another way, no matter how much money we had, we could find better ways of spending it than funding grants with bad scores. Instead of funding only 21 % of all approved applications, many of which shouldn't be funded,  we are more often funding 40 to 50 % of the good applications. Not too bad really. Reaching down could get you into bad territory.
It would be interesting if data were available on the age distribution of the PI's of grants that score better than 2 compared to those that score worse than 2.

It is in the best interests of both universities and the NIH to leave the system as is. But, NIH has so distorted the peer review process that it is faced with dilemmas like funding young investigators just because they are young not because of the merit of their ideas. The grant system has become an end in itself instead of a means to an end.

A Churchill quote about Democracy is often paraphrased to defend the current system as “the worst system ever invented except for every other system”. This may be true for democracy but not the NIH peer review system.

MORE ON THE NUMBER UNINSURED IN THE US

There was an exchange on the floor  of the house chamber between the President and Congressman Joe Wilson last night that bears on the figure of the number of people who are uninsured in this country.
The data used comes from the US census bureau and is 47 million.  I used the 47 million  figure to point out the various groups that make up this number using the same census bureau data. The 47 million figure includes 10 million people who , according to the Bureau , are " not American citizens".
Last night the  President vehemently said that his plan would not include the funding of health insurance for illegal alliens.
The President's speech should now automatically  lead everyone to reduce the figure of those without insurance  to 37 million..  Will it? I doubt it since it would tend to  reduce the urgency  to take down our entire health system for a mere 37 million uninsured, made up of four additional groups whose probelms can be solved by simple legislation. Actually , this morning he actually increased it!
As I said in my recent footnote to that blog, when it was reposted, I use these figures as a way to  judge whether any speaker actually knows what he or she is talking about vis a vis the health care issue..
So far it is slim pickings and it doesn't include the President or his advisors..